Influenza infection is a significant cause of morbidity and mortality worldwide. Our long-term goal is to identify intra- and extrapulmonary requirements for host defense and tissue protection in response to lung infections such as that caused by influenza. During influenza pneumonia, local pulmonary inflammation occurs in tandem with a systemic acute phase response (APR), typified by significant changes in circulating acute phase protein (APP) concentrations. However, remarkably little is known regarding the activation requirements and net functional significance of these diverse (and usually liver-derived) proteins as their blood signatures are altered in response to local infections. Our initial studies indicate that during influenza pneumonia, lung expression of the cytokines TNF, IL-1, and IL-6 correlates with viral burden and is followed by a dramatic induction of select APPs in the liver. These results suggest that liver APP synthesis is enabled by the decompartmentalization of these critical host defense cytokines from injured lungs into the circulation, where they ultimately gain access to hepatocytes. Here, we aim to determine the activation mechanisms and biological significance of liver-derived APPs during influenza pneumonia. To this end, we will address the following aims: 1) Test the hypothesis that the hepatic APR correlates with lung injury during influenza infection;2) determine whether the hepatic acute phase response depends on TNF, IL-1, and IL-6 during influenza pneumonia;and 3) determine whether the hepatic acute phase response and host defense is mediated by transcription factors STAT3 and RelA during influenza pneumonia. These aims will be accomplished by interrogating complementary indices of infection, injury, and host defense, all for which our laboratory is experienced. Notably, these studies will employ innovative mouse models in which mice are devoid of either cytokine signaling pathways (Aim 2), or liver transcription factors downstream of these cytokines (Aim 3). These studies will also greatly benefit from the expertise, mentorship, and cutting edge research environment provided by The Pulmonary Center at Boston University School of Medicine, which offers a long-standing and successful training platform for early investigators. Altogether, results obtained from the proposed research plan will provide significant insight regarding the hepatic response to lung influenza infection, how it is regulated, and the degree to which it is functionally significant, all within an environment where the candidate is poised to succeed. These findings may reveal novel therapeutic targets for the diagnosis, prevention and/or treatment of influenza. PUBLIC HEALTH RELEVANCE: Influenza infection is a major cause of respiratory disease worldwide and causes significant annual morbidity and mortality. During influenza pneumonia, local pulmonary inflammation occurs in concert with a systemic acute phase response. Understanding the activation pathways and the biological significance of this acute phase response can give us insights into potential mechanisms for prevention and treatment of this devastating illness.